Normal vocal fold vibration is crucially dependent upon tissue composition and viscoelasticity. When composition of the extracellular matrix (ECM) of the vocal fold cover (i.e. lamina propria - superficial and middle layers) is altered, vocal fold vibratory function can be severely disrupted due to alterations in tissue viscoelasticity. The dysphonias that result are generally difficult to treat effectively with current surgical paradigms and available biomaterials. Treatment failures have been ascribed to poor understanding of pathologic processes in the ECM, as well as suboptimal materials that may negatively affect vocal fold biomechanical properties. Accordingly, there is a clinical need for improved understanding of the pathophysiology of disrupted ECM and the development of advanced biomaterials that appreciate the biomechanical properties of the lamina propria. We have engineered injectable products that promote wound repair and induce tissue regeneration, both for prophylaxis and for treatment of scarring and other existing ECM defects of the lamina propria, exclusively for the superficial and middle layers. These products mimic and augment the existing ECM and yield optimal vocal fold ECM biomechanical properties. We have employed a unique combination of systematic chemical, biomechanical, in vitro and in vivo animal studies to resolve the complex interactions among tissue characteristics, biomechanical properties and surgical requisites necessary to create a suitable clinical outcome. However prior to the initiation of human trials it is vital that we evaluate the candidate therapeutics on human vocal fold fibroblast (VFF) immortalized cell lines to assess safety, tolerability and effectiveness. This translational milestone-driven R21 has 2 aims directly responsive to the PA criteria. Through our unique collaborations between basic scientists, clinical scientists and industry 1) We will develop a unique and rare in vitro tool for evaluation of VFF cellular and molecular mechanisms and 2) We will use this in vitro model to evaluate candidate hyaluronic acid (HA) hydrogels that we have engineered for promotion of wound healing and induction of tissue regeneration. Efforts from this R21 will provide imminent directions for an R01 focusing on human clinical trials for treatment of ECM disorders. [unreadable] [unreadable] [unreadable]